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Download Lecture 4: Mutant Characterization I Mutation types (and molecular
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Lecture 4: Mutant Characterization I Mutation types (and molecular nature) Complementation tests Read: 285-293 Fig. 8.28, 8.29, 8.30, 8.31 Terminologies: Minimal medium, complete medium Auxotroph vs. prototroph Hot spot, trinucleotide repeats ORF Silent, nonsense, missense, neutral mutations null, hypomorph, hypermorph, neomorph, antimorph recessive, dominant, dominant-negative, haploid-insufficient Homework#1 will be posted today! Fig. 8.28 • Mutations in a gene’s coding sequence can alter the gene product. – Missense mutations replace one amino acid with another. – Nonsense mutations change an amino-acid-specifying codon to a stop codon. – Frameshift mutations result from the insertion or deletion of nucleotides within the coding sequence. – Silent mutations do not alter amino acid specified. • Mutations outside of the coding sequence can also alter gene expression. – Promoter sequences – Termination signals – Splice-acceptor and splice-donor sites – Ribosome binding sites Fig. 8.28 b Terminology about different mutations a) Loss-of-function: Null mutation: complete absence of activity Hypomorph: reduced activity b) gain-of-function Hypermorph: increased activity Neomorph: new function of gene c) suppressors- compensate for other mutations d) enhancer- enhances phenotype of a mutation Fig. 8.29 1: null mutation; 2: hypomorphic mutation Both 1 and 2 are recessive The underlying nature of recessive or dominant mutations Recessive hypomorph: reduced level or a protein with a weak function Null: complete loss of function Dominant hypermorph: increased level or more effective activity neomorphic: new function dominant-negative: poisonous effect haploid-insufficient Ectopic expression Semi-dominant (incomplete dominant) Fig. 8.30 Incomplete dominance r0: null; r50: hypomorph; R+: wild type Rarely, loss-of-function mutations are dominant. • Haploinsufficiency – one wild-type allele does not provide enough of a gene product Fig. 8.31 a Heterozygotes for the null mutation of the T locus in mice have short tails because the have an insufficient amount of protein to produce a wild-type tail. Rarely, loss-of-function mutations are dominant. • Dominant-negative mutations – alleles of a gene encoding subunits of multimers that block the activity of subunits produced by normal alleles Fig. 8.31 b Kinky: A dominant-negative mutation in mice causing a kink in the tail Fig. 8.31 c Threshold For gain of function 3/3 3: hypermorphic mutation 3 is dominant 3/wt Gain-of-function mutations are almost always dominant. • Rare mutations that enhance a protein function or even confer a new activity on a protein Fig. 8.31 d Antennapedia is a neomorphic mutation causing ectopic expression of a leg-determining gene in structures that normally produce antennae. Determine recessive or dominant nature of the mutation c1c1 (Colorless mutant) X +/+ c1/+ X (red: recessive) (colorless: dominant) (self) Recessive 1/4 2/4 1/4 c1/c1 c1/+ + /+ (Red: WT) dominant colorless colorless colorless red red red Complementation tests “Complementation group” equals “Gene” If two mutations failed to complement, they are alleles of the same gene they are allelic to each other they belong to the same complementation group If two mutations complements each other, they are alleles of different genes they are not allelic to each other they belong to different complementation groups Determine allelism by complementation tests Pairwise crosses between homozygotes and examine F1 for phenotype only applicable for recessive mutations male c1c1 c2c2 c6c6 red red c1c1 colorless colorless red red red c2c2 colorless red red red c3c3 colorless red red c4c4 red red Maize kernel mutants: c1-c6: wt: colorless, recessive red c4c4 female c5c5 Colorless c3c3 colorless colorless colorless c5c5 colorless c6c6 Three complementation groups: 1. c1, c4 2. c2, c3 3. c5, c6